Elucidating Deregulated Novel Pathways in Glioma through Genetic and Epigenetic Approaches

Abstract

Malignancy of glial cells is termed as glioma. Gliomas comprise of thirty percent of all tumors of the central nervous system (CNS) and eighty percent of malignant brain tumors (Goodenberger and Jenkins, 2012). Astrocytoma, a type of glioma that arise from astrocytes, is the most common and lethal type of intracranial tumor. It is divided into four groups according to WHO (2007) classification based on histopathology. Grade I or pilocytic astrocytoma is benign in nature; however, the other three grades are progressively more malignant. Grade II or diffused astrocytoma is less aggressive and have a median survival of 5-8 years (Tove et al., 2012); while Grade III or anaplastic astrocytoma and glioblastoma (GBM) are classified under high grade gliomas with median survival of 2-3 years and 12-15 months respectively (Nuño et al., 2013; Arvold et al., 2014). GBM tumor is fast growing, highly infiltrative, and treatment refractory. It can be divided into two categories on the basis of their origin - primary GBM that accounts for 90 percent of GBM cases, manifest de novo without prior evidence of a pre-existing tumor of lower grade; while secondary GBMs develop through malignant progression of lower grade astrocytomas. Secondary GBMs typically exhibit genetic aberrations like TP53 mutation, IDH1 mutation, PTEN mutation, loss of chromosomal arm 10q etc. Primary GBMs show a whole host of genetic aberrations including EGFR amplification, PDGFR amplification, mutation in TP53, PTEN, NF1, RB etc., amplification of MDM2 and MDM4, loss of chromosomal arms 10p and 10q, CDKN2A and CDKN2B loss (Furnari et al., 2007). With the current treatment modality of GBM that includes surgical resection followed by radiotherapy and temozolomide chemotherapy, the median survival achieved till date is only 15 months and in almost all cases, the tumor recurs (Stupp et al., 2009). The aggressive and recurrent nature of GBM demands further insights into the molecular pathways deregulated in GBM. The changes that happen within a cell that lead to malignancy include both genetic and epigenetic alterations. Our objective is to delineate deregulated pathways in GBM progression and development through screening of genes via next generation sequencing (NGS) and methylome array. We further strive to characterize the importance of identified altered molecules and deregulated pathways in the context of GBM pathogenesis.